The tau protein is a microtubule-associated protein expressed, primarily, in the central nervous system. Its main function is stabilization of microtubules in these cells. More specifically, tau proteins interact with tubulin to stabilize it within the cells and promote tubulin assembly into microtubules.
There are six major isoforms of tau proteins expressed in the adult human, which are distinguished by the number of binding domains present at either or both the C-terminus and/or N-terminus of the protein. Three isoforms have three binding domains and three isoforms have four binding domains. These isoforms are derived from a single gene by alternative splicing.
Under pathological conditions, the tau protein becomes hyper-phosphorylated, resulting in a loss of tubulin binding and destabilization of microtubules. This is often followed by the aggregation and deposition of tau in pathogenic neurofibrillary tangles.
A number of disorders are related to tau proteins, particularly protein misfolding disorders, and are characterized by such pathological conditions. One example of such a disease includes Alzheimer's disease (AD), where hyper-phosporylation of the tau protein results in the self-assembly of tangles of paired helical filaments and strategy filaments. The role of such filaments in the progression of the disease is currently being studied and is unclear.
Immunotherapies targeting the beta-amyloid peptide in AD have produced encouraging results in animal models and shown promise in clinical trials. In the wake of success of Aβ-based immunization therapy in transgenic animal models, the concept of active immunotherapy was expanded to the tau protein. Active vaccination of wild type mice using the tau protein was found, however, to induce the formation of neurofibrillary tangles, axonal damage and mononuclear infiltrates in the central nervous system, accompanied by neurologic deficits. Subsequent studies in transgenic mouse lines using active vaccination with phosphorylated tau peptides revealed reduced brain levels of tau aggregates in the brain and slowed progression of behavior impairments. These findings highlight the potential benefit but also the tremendous risks associated with active immunotherapy approaches targeting tau. Novel therapeutic strategies are urgently needed addressing pathological tau proteins with efficacious and safe therapy.